Browsing by Subject "long-term depression"
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Item Estrogen-induced Signaling Links Structural and Functional Synaptic Plasticity(2009-05-01) Logan, Shaun M.; Simpkins, James W.It is well documented that of its many roles, estrogen can acutely alter the intrinsic and synaptic physiology of neuronal circuits in various regions of the brain. However, the molecular and cellular mechanisms by which estrogen couples electrophysiology to plasticity and memory are still not fully understood. Our data suggests a new possible mechanism by which estrogen, via L-type voltage-gated calcium channel (L-type VGCC) potentiation, modulates memory related synaptic plasticity. The rapid onset of 17β-estradiol (E2) action (less than one second) supports the hypothesis that E2 directly interacts with the channel protein. Several techniques allowed us to confirm that not only does E2 bind with high affinity to the L-type VGCC, but that it binds at a domain that overlaps with the dihydropyridine (DHP) site. Further, to determine whether E2-induced biochemical signaling mechanistically links synaptic plasticity, we studied the phosphorylation patterns of structural and functional plasticity related proteins (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors [AMPAR], AMPA-type glutamate receptor subunit 1 [GluR1], calcium/calmodulin-dependent protein kinase II [CaMKII], and extracellular signal-related kinase [ERK]). E2 rapidly increased phosphorylation of CaMKII, ERK, and AMPAR in primary cortical neurons and in vivo in the cortex. The CaMKII inhibitor (KN-93) decreased phosphorylation levels of GluR1 in primary cortical neurons. We also determined that soluble amyloid-beta (Aβ)1-42 oligomers abrogated, while E2 ameliorated phosphorylation of GluR1 at its CaMKII site. Aβ treatment also inhibited GluR1 trafficking, but E2 prevented this inhibition. Due to our observation that E2 treatment rapidly increased spine number and ameliorated Aβ-induced spine loss, we concluded that estrogen-induced signaling does in fact mechanistically link structural and functional plasticity. In comparison with the cortical data (in vitro and in vivo), we found that E2 treatment in hippocampal slice culture ameliorated Aβ oligomer-induced inhibition of CaMKII and AMPAR phosphorylation, reduction of dendritic spine density, and abnormalities in LTP-induced spine growth. Taken together, these results suggest that acute estrogen treatment has the potential to prevent Aβ oligomer-induced synaptic dysfunction.Item Translational Control by Estrogen-Induced Signaling in Primary Rat Hippocampal Neurons(2008-07-01) Smith, Lonell T.; Simpkins, James; Das, Hriday K.; Machu, Tina K.Smith, Lonell T., Estrogen-Induced Signaling in Primary Rat Hippocampal Neurons. Masters (Biomedical Sciences). July 2008. 53 pages, 1 illustration, 7 figures. 37 titles. Abstract. The enhancing effects of 17-beta estradiol (E2) on performing cognitive tasks has been well demonstrated in laboratory mice, rats, and primates. Also there is ample clinical evidence indicating E2 enhances memory and reduces risk for Alzheimer’s disease. Furthermore, by increasing the capacity for long-term potentiation (LTP) in the hippocampus, E2 effectively increases the synaptic plasticity of this brain region in a manner that correlates with memory formation. The molecular mechanisms underlying LTP and synaptic plasticity have largely focused on the role of E2-induced signal transduction in the nucleus, and regulation of plasticity related gene expression at the transcriptional level. Conversely, the idea that E2-incuded signaling regulates at the level of translation and may play a role in these processes has yet to be explored. Recently, extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) signaling pathways have been shown to couple synaptic activation to protein synthesis machinery. Here we investigate translational control by E2-induced ERK and mTOR signaling in primary neuronal culture. E2-induced signaling resulted in enhanced phosphorylation of ribosomal protein (S6) and eIF4E binding protein 1 (4EBP1) in an ERK and mTOR-dependent manner. Neuronal activity-dependent ERK and mTOR signaling have been shown to induce translation of a diverse array of dendritic resident mRNAs, including α-CaMKII and GluR1 subunits. Using a green fluorescent protein (GFP) translational reporter, we demonstrated that E2 stimulates GFP protein synthesis. We have also demonstrated that E2 treatment of hippocampal neurons increases surface expression of GluR1. Taken together, our results provide a mechanism by which E2 modulates the components necessary for persistent forms of LTP and long-term depression (LTD).